A need for the site-specific delivery of pharmacological agents is well known in many fields of medicine. When using chemotherapeutic agents, for example, a major concern is their toxicity to non-target cells. Thus, a site-specific carrier is needed that will deliver a chemotherapeutic agent capable of killing targeted cells without killing surrounding healthy cells.
NO is a good chemotherapeutic agent because intracellular concentrations of NO have been shown to be deleterious to tumor cells. In addition, NO has shown potential benefits in post-arteriosclerosis therapy, wound healing, impotence therapy, and other therapies. Site-specific delivery is often medically preferred, however, because many pharmacological agents, such as NO, can be toxic.
The wound healing process is a complicated orchestration of a series of physiological responses, including an inflammatory response, angiogenesis, the development of fibrous tissue, and re-epithelization LaVan et al., Wound Healing, 17 (3):463 (1990). NO is both directly and indirectly involved in each of these physiological processes. Vitamin B.sub.12 is also known to enhance wound healing.
Vitamin B.sub.12 compounds are naturally occurring, non-immunogenic, non-toxic vitamins that are present in the human body. Vitamin B.sub.12 compounds are known to have many biological functions. They are required by the enzyme methionine synthase, for example, which is involved in the production of DNA. Pregnant women need increased amounts of B.sub.12 which is involved in the production of red blood cells. It is also believed that vitamin B.sub.12 enhances the effects of other vitamins and nutrients in tissue repair.
Currently, polymeric NONOates are growing in popularity as prospective NO donors because they are able to sustain elevated levels of NO in vivo over extended periods of time. Many polymeric NONOates, however, can be toxic. After nitric oxide release these polymers degrade, often causing an inflammatory response and other adverse tissue reactions.
Another drawback of conventional NO-donors is that they are limited in the conditions under which they can be used. These donors generally release NO without specificity under physiological conditions; thus, they release NO as soon as they enter the body. Therefore, there is a need for site-specific, biologically compatible donors of NO that have less harmful side effects.
Metallocorrinoids are corrin rings with a metal-atom center, such as Co, Fe, Ni, or Mn. A corrin ring is four reduced pyrrole rings linked together as shown in FIG. 1. A subclass of naturally occurring metallocorrinoids found in the human body is a cobalamin, that is, a cobalt-centered corrin ring. Many cobalamins related to vitamin B.sub.12 compounds are a subclass of cobalamin that includes hydroxocobalamin, cyanocobalamin, nitrocobalamin, methylcobalamin, and 5'-deoxyadenocobalamin.
It is generally known that NO will bind to a cobalamin. Heretofore, it has been attempted to use a cobalamin, such as hydroxocobalamin, as a scavenger of NO. For example, PCT Application No. WO95/31204 (Greenburg et al.) discloses a process whereby hydroxocobalamin is added to an NO-rich site in vivo. Hydroxocobalamin then binds the NO, thereby decreasing the concentration of potentially harmful NO at the site. Heretofore, however, nitrosylcobalamin has not been synthesized, isolated, purified, or used to deliver NO.